Adult osteoporosis with a history of childhood-onset fracture due to an lrp5 receptor variant mutation

This case highlights the value of genetic screening for idiopathic osteoporosis with recurrent fractures. This case highlights the variability in clinical expression of LRP5 polymorphisms and suggests that standard treatment in cases of recurrent fracture may be ineffective. (AACE Clinical Case Rep. 2019;5:e362-e364)

Case Report ADULT OSTEOPOROSIS WITH A HISTORY OF CHILDHOOD-ONSET FRACTURE DUE TO AN LRP5 RECEPTOR VARIANT MUTATION Terry Shin, MD, MAJ1; Jay R Shapiro, MD2 ABSTRACT CASE REPORT Objective: This case highlights the value of genetic screening for idiopathic osteoporosis with recurrent fractures Methods: Case report and review of the literature Results: A 52-year-old Caucasian female with idiopathic osteoporosis with recurrent fractures was identified with a heterozygous low-density lipoprotein receptor related protein (LRP5) mutation Conclusion: This case highlights the variability in clinical expression of LRP5 polymorphisms and suggests that standard treatment in cases of recurrent fracture may be ineffective (AACE Clinical Case Rep 2019;5:e362-e364) A 52-year-old Caucasian nulliparous woman with a history of osteoporosis was evaluated in the clinic for recurrent fractures despite antiresorptive and anabolic therapy She initially suffered her first nontraumatic fracture at age in her tibia with subsequent nontraumatic fractures at age 13, 18, and 24, involving the patella, clavicle, and ribs She developed a fracture of her humerus at age 35, a pelvic fracture at age 36, a heel fracture at age 49, and a metatarsal fracture at age 50 She was treated with alendronate for year at age 45, and zoledronic acid for year at age 46 A trial of teriparatide was initiated at age 49 for months but was discontinued due to the development of nonspecific gastrointestinal symptoms She received topical estradiol patch therapy for approximately years starting at age 47 for unknown reasons Surgical history was notable for a partial hysterectomy at age 44 for anovulatory bleeding Additional surgeries included right ankle surgery and foot surgery Family history was notable for a mother who was osteoporotic and also experienced recurrent nontraumatic fractures Physical examination of the patient was unremarkable with normal vital signs, white sclerae, normal ophthalmologic examination, normal dentition, and no gross skeletal deformities Biochemical screening that included a complete blood count, renal panel, thyroid panel, corrected calcium, and alkaline phosphatase were within normal limits Osteocalcin levels were not tested at the time of evaluation She was found to have an elevated urinary N-terminal telopeptide (NTX) level at 105 nmol BCE/mmol creatinine (normal, to 65 nmol/BCE/mmol creatinine for a premenopausal female) Postmenopausal urinary NTX reference ranges were not available at the reference lab at time of testing Available dual-energy X-ray absorptiometry (DXA) study at age 45 reported a T-score in the lumbar spine at –3.2, in the left hip at –3.2, and in the left femoral Abbreviations: LRP5 = low-density lipoprotein receptor related protein 5; SNP = single nucleotide polymorphism Submitted for publication May 11, 2019 Accepted for publication July 11, 2019 From 1Walter Reed National Military Medical Center, Bethesda, and 2Uniformed Services University of the Health Sciences, Bethesda, Maryland Address correspondence to Dr Terry Shin, Walter Reed Military Medical Center, 8901 Rockville Pike, Bethesda, MD 20889 E-mail: terry.shin.mil@mail.mil DOI: 10.4158/ACCR-2019-0219.R1 To purchase reprints of this article, please visit: www.aace.com/reprints Copyright © 2019 AACE e362 AACE CLINICAL CASE REPORTS Vol No November/December 2019 Copyright © 2019 AACE Copyright © 2019 AACE Osteoporosis from LRP5 Mutation, AACE Clinical Case Rep 2019;5(No 6) e363 neck at –3.4 Plain film imaging of the cervical, thoracic, and lumbar spine revealed a slight loss of height at C3 to C6, minimal anterior wedging in the lower thoracic vertebral bodies, generalized osteopenia, and multiple healed rib fractures A genetic screen for osteogenesis imperfecta was negative and genetic workup revealed a mutation in the gene encoding low-density lipoprotein receptor related protein (LRP5; chromosome 11 in-frame duplication, exon 1, c.52_60dup Leu18_Leu20dup, involving allele) The patient was planned for trial of an alternative antiresorptive therapy, but she was lost to follow-up DISCUSSION Failure to improve bone mass on DXA and occurrence of recurrent fractures in the setting of conventional osteoporosis treatment should raise questions about the underlying cause of osteoporosis irrespective of age or gender of the affected individual In an analysis of factors associated with osteoporosis treatment failures, Diez-Pérez et al (1) highlighted the following variables predictive of treatment failure: low SF-36 vitality score, or more falls within in the past year, and prior fracture Our patient had an elevated vitality score and experienced multiple fractures starting in early childhood, an important fact that was overlooked in earlier evaluations Clinical features suggestive of osteogenesis imperfecta or endocrine disorder were not present in this patient, and her history ultimately led to further investigation via genetic testing identifying an LRP5 mutation LRP5 is a coreceptor along with low-density lipoprotein related protein and the frizzled family of transmembrane receptors that facilitate Wnt protein activated Wnt/β-catenin signaling in the Wnt signaling pathway (2) Components of the Wnt pathway are essential for normal bone development including osteoblast differentiation and function, osteocyte directed bone formation, and osteoclast bone resorption (3) LRP5-mediated Wnt signaling significantly contributes to maintenance of bone mass and bone mechanical properties (4) The role of LRP5 in osteoblast function is illustrated in murine studies in which Cre recombinase-mediated LRP5 gene recombination is associated with a decrease in whole-body bone mineral density and a deficiency in trabecular and cortical bone mass with increasing age (5) Gain-of-function mutations in LRP5 lead to increased bone density known as sclerosteosis and van Buchem syndrome These conditions are also characterized by elevated bone density, hyperostosis with mandibular enlargement, and thickening of the skull (6,7) Roetzer et al (8) reported high bone mass associated with an LRP5 gain-of-function mutation in a 53-year-old mother and her 23-year-old daughter These patients also had increased calvarial thickness and thickened long bone cortices without any history of fractures (8) Loss-of-function mutations of LRP5 in osteocytes are associated with suppression of mechanoresponsiveness to mechanical loading and a decrease in Young’s modulus leading to low bone mass (5) Homozygous loss-of-function mutations of the LRP5 receptor are associated with the osteoporosis-pseudoglioma syndrome Heterozygous LRP5 mutations are known as juvenile onset osteoporosis (9) This patient did not have features of the homozygous LRP5 loss-of-function mutation known as osteoporosis pseudoglioma/familial exudative vitreoretinopathy syndrome, but she did mirror case reports of juvenile-onset primary osteoporosis (10,11) These patients are known to have a heterozygous missense or frameshift LRP5 mutation and this explains the early occurrence of fractures in this patient (10,11) Several studies report single nucleotide polymorphisms (SNPs) involving the LRP5 receptor in women with age-related osteoporosis (12) In 2008, collaborators in the GENOMOS study assessed the association of LRP5 variants (Val667Met, and Ala1330Val) with bone mineral density (BMD) and fracture risk in 37,534 individuals from 18 participating teams in Europe and North America (13) Both the Met667 and Val667met allele of LRP5 was associated with reduced lumbar spine femoral neck BMD (12) However, the role of LRP5 mutations as the etiology of spine or hip fractures remains unclear Riancho et al (14) analyzed 39 single nucleotide LRP5 SNPs in a group of 1,043 postmenopausal women and 394 women with hip fractures (14) Several LRP5 SNPs were associated with vertebral fractures (odds ratio [OR] 0.67; P = 01) and with hip fractures (unadjusted ORs between 0.59 and 1.21; P = 005 to 033), but were not significant after multivariate analysis adjusted for age and height (14) Thus, while several polymorphisms of the LRP5 gene tend to be associated with fractures, the significance remains to be determined It is clear, however, that patients with recurrent fractures at a young age may have an underlying mutation variant in LRP5 CONCLUSION In summary, we report a unique case of a woman with recurrent unexplained osteoporotic fractures despite antiresorptive and anabolic treatment of osteoporosis in the setting of LRP5 mutation This case raises several questions First, how common does this LRP5 polymorphism occur in treatment-refractory osteoporosis with recurrent fractures? Second, what is the basis for the marked variability in the clinical expression of LRP5 polymorphisms? And third, what interventions could help limit fracture risk in this genetic disorder? Clinicians should consider referral to a geneticist for genetic testing in patients with unexplained fractures which could lead to early identification and potential prevention treatment strategies for this unique patient population As genetic testing for the LRP5 e364 Osteoporosis from LRP5 Mutation, AACE Clinical Case Rep 2019;5(No 6) mutation is limited, we believe the accessibility of LRP5 testing should be expanded in commercial labs given the possibility of a higher prevalence of disease in this unique patient group Though there has been no reported use in this specific condition, the recent development of antisclerostin antibodies may theoretically be a therapeutic option for these patients through direct targeting of the Wnt LRP5/6 signaling pathway The patient described in this case was planned for trial on antisclerostin therapy, but she was lost to follow-up DISCLOSURE The authors have no conflicts of interest to disclose We certify that all individuals who qualify as authors have been listed; that each has participated in the conception and design of this work, the analysis of data, the writing of the document, and the approval of the submission of this version; that the document represents valid work; that if we used information derived from another source, we obtained all necessary approvals to use it and made appropriate acknowledgements in the document; and that each takes public responsibility for it The authors are employees of the United States Government This work was prepared as part of their official duties Title 17 U.S.C §105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C §101 defines a U.S Government work as a work prepared by a military service member or employee of the U.S Government as part of that person’s official duties The views expressed in this article are those of the authors and not necessarily reflect the official policy or position of the Departments of the Navy/Army/Air Force, Uniformed Services University of the Health Sciences, the Department of Defense, or the U.S Government Copyright © 2019 AACE REFERENCES Diez-Pérez A, Naylor KE, Abrahamsen B, et al International Osteoporosis Foundation and European Calcified Tissue Society Working Group Recommendations for the screening of adherence to oral bisphosphonates Osteoporos Int 2017;28:767-774 Canalis E Wnt signalling in osteoporosis: mechanisms and novel therapeutic approaches Nat Rev Endocrinol 2013;9:575-583 Riddle RC, Diegel CR, Leslie JM, et al Lrp5 and Lrp6 exert overlapping functions in osteoblasts during postnatal bone acquisition PLoS One 2013;8:e63323 Williams BO LRP5: from bedside to bench to bone Bone 2017;102:26-30 Zhao L, Shim JW, Dodge TR, Robling AG, Yokota H Inactivation of Lrp5 in osteocytes reduces young’s modulus and responsiveness to the mechanical loading Bone 2013;54:35-43 Beighton P, Barnard A, Hamersma H, van der Wouden A The syndromic status of sclerosteosis and van Buchem disease Clin Genet 1984;25:175-181 Korvala J, Jüppner H, Mäkitie O, et al Mutations in LRP5 cause primary osteoporosis without features of OI by reducing Wnt signaling activity BMC Med Genet 2012;13:26 Roetzer KM, Uyanik G, Brehm A, et al Novel familial mutation of LRP5 causing high bone mass: genetic analysis, clinical presentation, and characterization of bone matrix mineralization Bone 2018;107:154-160 Gong Y, Slee RB, Fukai N, et al LDL receptor-related protein (LRP5) affects bone accrual and eye development Cell 2001;107:513-523 10 Franceschi R, Vincenzi M, Camilot M, et al Idiopathic juvenile osteoporosis: clinical E experience from a single centre and screening of LRP5 and LRP6 genes Calcif Tissue Int 2015;96:575-579 11 Hartikka H, Mäkitie O, Männikkö M, et al Heterozygous mutations in the LDL receptor-related protein (LRP5) gene are associated with primary osteoporosis in children J Bone Miner Res 2005;20:783-789 12 Pyott SM, Tran TT, Leistritz DF, et al WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta Am J Hum Genet 2013;92:590-597 13 van Meurs JB, Trikalinos TA, Ralston SH, et al Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis JAMA 2008;299:1277-1290 14 Riancho JA, Olmos JM, Pineda B, et al Wnt receptors, bone mass, and fractures: gene-wide association analysis of LRP5 and LRP6 polymorphisms with replication Eur J Endocrinol 2011;164:123-131  ... osteogenesis imperfecta Am J Hum Genet 2013;92:590-597 13 van Meurs JB, Trikalinos TA, Ralston SH, et al Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis JAMA 2008;299:1277-1290... identifying an LRP5 mutation LRP5 is a coreceptor along with low-density lipoprotein related protein and the frizzled family of transmembrane receptors that facilitate Wnt protein activated Wnt/β-catenin... the LRP5 receptor in women with age-related osteoporosis (12) In 2008, collaborators in the GENOMOS study assessed the association of LRP5 variants (Val667Met, and Ala1330Val) with bone mineral